1. Field of the Invention
The present invention general concerns the endocrinology, more specifically methods for maintaining blood sugar homeostasis.
2. Description of Related Art
Regulation of glucose homeostasis in the bloodstream must be tightly controlled to maintain healthy metabolic function. Low serum glucose levels (hypoglycemia) can lead to weakness, headaches, confusion and if unchecked ultimately convulsions, coma and death. On the other hand, hyperglycemia causes excess urine production, thirst, weight loss, fatigue, and in sever cases can also result in coma and death. Chronically high blood sugar also can result in long term tissue damage that may contribute to diabetic complications such as blindness, kidney failure, impotence, atherosclerosis, and increased vulnerability to infection.
In a healthy subject pancreatic tissue is responsible for secretion of hormones that regulate serum glucose homeostasis. After a meal, when blood glucose levels rise, secretion of insulin lowers blood sugar by stimulating tissue glucose uptake (the primary tissue responsible being skeletal muscle). Conversely, when serum glucose levels fall secretion of glucagon stimulates the liver to release stored glucose into the blood stream.
Diabetes mellitus is an increasingly common disorder around the world, characterized by chronically elevated serum glucose levels. Classically, diabetes segregates into two distinct groups that require alternative therapeutic approaches. Type 1 diabetes, as known as insulin-dependent diabetes mellitus, is primarily caused by an inability of the subject to produce sufficient insulin to regulate blood sugar. On the other hand, type 2 diabetes, non-insulin-dependent diabetes, is characterized by an inability to respond to elevated serum insulin, a state know as insulin resistance. Both diabetic conditions are greatly exacerbated by clinical obesity, and likewise obesity is a risk factor to the development of type 2 diabetes.
Insulin resistance is a characteristic feature in the pathogenesis of diseases such as type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease, polycystic ovarian syndrome and obesity though the molecular mechanisms causing these diseases are not fully understood (Spiegelman and Flier, 2001; Friedman, 2004; Bouche et al., 2004; Evans et al., 2004; Bhatia 2005; Bugianesi et al., 2005). However, impaired whole body glucose uptake plays a significant role in insulin resistance (Seely and Olefsky, 1993; Shulman, 2000; Virkamaki et al., 1999). Skeletal muscle constitutes the largest insulin-sensitive tissue mammals and thus insulin resistance in this organ has the largest impact on whole body glucose homeostasis (Shulman, 2004; Zierath et al., 2000). Although major advances have been made in the molecular mechanisms of insulin action in muscle, little is known of local muscle factors that can modulate glucose transport. Recently however, it was shown that mice lacking the protein corticotropin-releasing factor receptor 2 (CRFR2) displayed changes in insulin-sensitivity, suggesting a possible role for CRFR2 in blood sugar homeostasis (Bale et al., 2003). Additionally, CRFR2 is expressed as a variety of protein isoforms (CRFR2α, CRFR2β, CRFRγ), some of which are selectively expressed in certain tissues (Kostich et al., 1998). In general, it is known that CRFR2 is primarily expressed in heart and skeletal muscle. However, the role of CRFR2 signaling in regulation of serum glucose levels was still unclear (Perrin and Vale, 1999; Chen et al., 2005).
Corticotropin releasing factor receptors are the physiological receptors for the corticotropin-releasing factor (CRF) family peptides that have been suggested to play a role in modulating energy homeostasis (Brown et al., 1982; Dallman et al., 1995; Bale et al., 2003; De Kloet, 2004). Urocortin 2 (Ucn 2), a recently identified member of the CRF family (Reyes et al., 2001; Hsu and Hsueh, 2001), is highly expressed in skeletal muscle though the physiological functions of Ucn 2 in this tissue are not known (Chen et al., 2004). Interestingly, the effects of Ucn 2 are primarily mediated through activation of its high affinity, membrane receptor CRFR2 (Perrin et al., 1995; Kishimoto et al., 1995). A related CRF family member Urocortin 3 also acts as a CRFR2 agonist, and is expressed primarily in the pancreas. The invention described herein elucidate the role CRFR2 signaling in regulation of serum glucose homeostasis and insulin-sensitivity.